title: Impact of parenteral nutrition versus fasting on hepatic bile acid production and transport in a rabbit model of prolonged critical illness.
abstract: BACKGROUND
  Cholestatic liver dysfunction frequently occurs during critical illness. Administration of parenteral nutrition (PN) is thought to aggravate this. Underlying mechanisms are not clear.
  
  
  METHODS
  In a burn model of prolonged critical illness, rabbits were randomized to a nutritional strategy either accepting caloric deficits (fasted, n = 11) or covering caloric needs by PN (fed, n = 10). At baseline and after 7 days of critical illness, markers of hepatotoxicity, circulating bile acids, and the hepatobiliary transport system were studied.
  
  
  RESULTS
  Fasted animals had lower circulating alanine aminotransferase/aspartate aminotransferase levels than did the fed animals at day 7. Compared with baseline values, fed animals displayed lower serum unconjugated cholic acid (CA) and deoxycholic acid (DCA) levels. Unconjugated DCA remained unaltered in fasted animals. Unconjugated lithocholic acid was increased comparably in all animals, whereas hyodeoxycholic acid was not altered. In contrast, fasting induced a shift from unconjugated CA and DCA to glyco-CA and glyco-DCA. Total bile acids did not correlate with the bile acid-producing enzyme CYP7A1, but with the basolateral efflux transporter MRP3. Fasting increased protein expression of the basolateral (MRP3) and the canalicular (BSEP) transporter, whereas the canalicular efflux pump MRP2 was suppressed. Gene expression levels of the nuclear receptor farnesoid X receptor were lower with fasting and correlated inversely with MRP3. The heterodimer partner of farnesoid X receptor, retinoid X receptor α, was increased with fasting and correlated positively with MRP3.
  
  
  CONCLUSIONS
  During prolonged critical illness, withholding PN improved markers for hepatocyte injury and accentuated bile acid transport toward the blood. This suggests that the latter is an adaptive rather than a dysfunctional feedback to illness.
authors.affiliation: *Laboratory and Department of Intensive Care Medicine, University Hospitals KU Leuven, Leuven, Belgium; and †Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia.
authors.forename: Yoo-Mee
authors.initials: YM
authors.lastname: Vanwijngaerden
authors.forename: Lies
authors.initials: L
authors.lastname: Langouche
authors.forename: Sarah
authors.initials: S
authors.lastname: Derde
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.forename: Sally
authors.initials: S
authors.lastname: Coulter
authors.forename: Greet
authors.initials: G
authors.lastname: van den Berghe
authors.forename: Dieter
authors.initials: D
authors.lastname: Mesotten
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000097:blood; D001663:Bilirubin / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D015415:Biomarkers / Q000097:blood; D002779:Cholestasis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D016638:Critical Illness / Q000628:therapy*; D004195:Disease Models, Animal; D005215:Fasting / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000097:blood; D010288:Parenteral Nutrition / Q000009:adverse effects; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics; D047490:Retinoid X Receptor alpha / Q000096:biosynthesis / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D001647:Bile Acids and Salts; D001663:Bilirubin; D015415:Biomarkers; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D047490:Retinoid X Receptor alpha; D000099150:Receptor, Farnesoid X-Activated; C114462:multidrug resistance-associated protein 3